Papillomaviruses, by virtue of their chosen type of host cell, avoid much of the body’s immune response. Keratinocytes have a short lifespan, the culmination of which is programmed cell death, or apoptosis; since the body uses apoptosis as a mechanism for healthy cell maintenance, immune cells are not stimulated by this process as they are by cell destruction. By waiting until the keratinocytes are dead or dying to begin expressing its assembly proteins, the newly assembled virions can exit the cell without the accompanying inflammation and immune response that outright killing the cell would initiate. As well, this death occurs in the superficial epithelium, which is far from the patrolling leukocytes and Langerhans cells (LC) that might detect the virus (Stanley 2006). Since natural killer (NK) cells kill infected cells more effectively once the late viral coat proteins are expressed (Oldak et al. 2004), and they are mostly found in the subepithelial layers of the skin (Tay et al. 1987), this movement away from the immune surveillance areas also evades the destruction of the host cell and the subsequent triggering of the innate response.

HPV also limits detection by LC and reduces inflammation during development by inhibiting the keratinocyte’s synthesis of IFN-α and -β, as well as macrophage inflammatory protein-3α (MIP-3α) (Guess & McCance 2005). Without these inflammatory cytokines, the LCs become acclimatized to the presence of the virus in low quantities, thus slowing the immune response (Stanley 2006). There is also evidence that infected keratinocytes produce lower levels of granulocyte-macrophage colony-stimulating factor (GMCSF) and tumor necrosis factor (TNF), which promote LC migration and maturation. To decrease the adaptive immune response after LCs have noticed the infection, the virus inhibits the number of surface signaling molecules (MHC-1) that the keratinocyte expresses, which limit the ability of activated cytotoxic T cells to kill the infected cell (Scott et al. 2001). Though this lack of MHC-1 molecules would normally activate natural killer (NK) cells to kill these cells, few NKs patrol the upper epithelial layers and thus rarely come into contact with the infected keratinocytes.